On September 11, 2017 Transgene (Paris:TNG), a biotech company that designs and develops viral-based immunotherapies, reported that the US Food and Drug Administration (FDA) has granted Transgene Investigational New Drug (IND) clearance to proceed with a Phase 2 clinical trial of TG4010 in combination with Opdivo (nivolumab) and chemotherapy as a first-line treatment for advanced non-squamous non-small cell lung cancer (NSCLC) in the USA (Press release, Transgene, SEP 11, 2017, View Source [SID1234520473]).

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The Phase 2 clinical trial will explore the potential of combining Transgene’s TG4010, an investigational therapeutic vaccine, in association with Bristol-Myers Squibb’s immune checkpoint inhibitor, nivolumab, which acts by overcoming immune suppression. Both therapies will be combined with standard chemotherapy in first-line NSCLC patients, whose tumors express low and undetectable levels of PD-L1.

Transgene is the sponsor of this international trial. Transgene has signed a clinical collaboration agreement with Bristol-Myers Squibb, which will provide nivolumab for the study (see press release dated April 25, 2017).

The Phase 2 trial will evaluate objective tumor responses and disease control. The study will also assess the safety and tolerability of the regimen together with other efficacy parameters. This multi-center single-arm trial will enroll patients both in the USA and Europe.

The first patient is expected to be included into this Phase 2 study at the end of 2017.

"We are very pleased that the FDA approval for the trial combining TG4010, nivolumab and chemotherapy as a first-line treatment of non-squamous NSCLC has been granted to Transgene" said Maud Brandely, Chief Medical Officer of Transgene. "Advanced lung cancer remains a high medical need, in particular for patients whose tumors express low or undetectable levels of PD-L1. We are looking forward to advancing this clinical trial and evaluate the potential of this triple combination regimen as a better treatment option for these patients."

About TG4010
TG4010 is an immunotherapy that has been designed to express the coding sequences of the MUC1 tumor-associated antigen and the cytokine, Interleukin-2 (IL2). It is based on a modified vaccinia virus (MVA), and has been shown to induce an immune response against MUC1 expressing tumors, such as non-small cell lung cancer (NSCLC).
The combination of TG4010 immunotherapy and chemotherapy has demonstrated significant efficacy in terms of progression-free survival and overall survival in patients with advanced stage NSCLC. The results from the Phase 2b TIME trial with TG4010 in conjunction with chemotherapy in NSCLC have been published in the peer-reviewed medical journal, The Lancet Oncology in December 2015.

About Non-Small Cell Lung Cancer
Lung cancer is one of the most common malignancies worldwide with an estimated 1.8 million new cases annually. It is also a leading cause of cancer-related deaths, accounting for an estimated nearly 1.6 million deaths in 2012 (Source: GLOBOCAN 2012). Advanced lung cancer remains one of the cancer types with the worst prognosis (five-year survival rate for advanced NSCLC of less than 5%), underlining the still unmet need in this disease.

On September 11, 2017 TESARO, Inc. (NASDAQ:TSRO), an oncology-focused biopharmaceutical company, reported a summary of ZEJULA and TSR-042, an anti-PD-1 antibody, data presented at the 2017 European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Annual Meeting in Madrid (Press release, TESARO, SEP 11, 2017, View Source [SID1234520472]).

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"ZEJULA is the market-leading PARP inhibitor, with unsurpassed efficacy in a broad patient population and convenient, once-daily dosing," said Mary Lynne Hedley, Ph.D., President and COO of TESARO. "‘Watchful waiting’ is no longer an acceptable option for women living with ovarian cancer. We believe combination approaches, including niraparib and anti-PD-1 antibodies, will become increasingly important and we are executing on our registration strategy for TSR-042, our anti-PD-1 antibody, in MSI-high cancers."

ZEJULA (niraparib) presentations:

Treatment with niraparib did not impact patient quality of life in the NOVA trial
Quality of life measures are important to understanding the benefit of niraparib in the maintenance treatment setting. Dr. Amit M. Oza, M.D., Senior Staff Physician, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, presented quality of life (QoL) data from the Phase 3 ENGOT-OV16/NOVA trial. Patient-reported outcomes (PROs) were evaluated along with individual patient-reported symptoms using the Functional Assessment of Cancer Therapy-Ovarian Symptoms Index (FOSI) and European Quality of Life Scale 5-Dimensions (EQ-5D-5L). The most common PRO symptoms at baseline were fatigue and pain, and 20% of patients experienced nausea at baseline. No significant difference in mean patient-reported outcomes (PRO) scores was observed between patients treated with niraparib versus placebo, regardless of germline BRCA mutation status. Hematologic adverse events (thrombocytopenia, neutropenia, anemia) decreased over time with dose modification and did not impact QoL. These results also suggest that patients with ovarian cancer often experience residual symptoms of their disease following the conclusion of chemotherapy.

Safety and efficacy of niraparib in elderly patients comparable to overall population in NOVA
In a poster discussion session, safety and efficacy results from the ENGOT-OV16/NOVA trial were highlighted for a sub-group of elderly patients, aged 70 years and older. In this post-hoc analysis, the efficacy of niraparib was similar for patients aged <70 years compared to patients aged ≥70 years in both the gBRCAmut and non-gBRCAmut cohorts. Grade ≥3 treatment-emergent adverse events (TEAEs) occurring in >10% of niraparib treated patients were also consistent between the two groups, and dose reductions, interruptions, and treatment discontinuations occurred with similar frequency, regardless of age. These results demonstrate that niraparib may provide clinical benefit to a broad population of patients with ovarian cancer irrespective of age.

Niraparib exposure — response findings support dosing patients at individually adjusted maximal tolerated dose
In a poster discussion session, the relationship between niraparib exposure and efficacy, as well as exposure and safety, was highlighted in patients enrolled in the ENGOT-OV16/NOVA trial. Efficacy as measured by PFS was compared in patients with high exposure (defined as greater than median exposure) versus low exposure (defined as less than or equal to median exposure). Patients experienced similar efficacy at their individual maximum tolerated dose regardless of the dose received. Reaching maximal exposure for individual patients, as was done in the ENGOT-OV16/NOVA trials via dose modifications, was likely an important factor in achieving maximal efficacy, especially for patients without a BRCA mutation. Limited exposure-efficacy association was observed among patients who were germline BRCA mutation carriers, while the exposure-efficacy association was more apparent for patients who were not germline BRCA mutation carriers. On a population level, the incidence of treatment-emergent adverse events (TEAEs) was higher with increased dose. These findings support that patients, especially those with BRCA wild-type tumors, should be treated at their individually adjusted maximal tolerated dose to provide the optimal chance of efficacy.

Model highlights niraparib pharmacokinetic properties, including high tissue distribution and slow elimination, and no need for dose adjustments in patients with mild-to-moderate renal or hepatic impairment
In a poster display session, data from the Phase 1 dose-escalation and expansion studies (n=104) and the Phase 3 ENGOT-OV16/NOVA study (n=408) of niraparib were used to model the impact of patient variables (age, race, ethnicity, body weight), renal impairment (normal, mild, or moderate), and hepatic function (baseline serum alanine and aspartate aminotransferase, albumin, total bilirubin) on niraparib pharmacokinetic parameters. In the base model, the typical value for niraparib apparent clearance was 16.2 L/h, with inter-individual variability of 52.6%. The estimated volume of distribution was 1074 L (290 L central and 784 L peripheral compartment). None of the patient variables impacted niraparib pharmacokinetics, including mild-to-moderate renal impairment and mild hepatic impairment, and model diagnostics showed good agreement between predicted and observed individual niraparib plasma concentrations. These results demonstrate that no dose adjustments are needed for patients treated with niraparib with mild-to-moderate renal or hepatic impairment.

Bevacizumab-niraparib combination demonstrated preliminary evidence of activity and a predictable adverse event profile
Updated data from the ongoing Phase 2 AVANOVA study of bevacizumab plus niraparib, an Investigator Supported Trial (IST), in patients with platinum sensitive recurrent ovarian cancer (n=12) demonstrated activity and a predictable adverse event profile. In the first cycle (21 days) of the study, patients experienced expected and manageable adverse events including anemia, constipation, fatigue, hypertension, nausea and thrombocytopenia. One dose-limiting toxicity (grade 3 thrombocytopenia) was observed at the highest dose level. Three patients were dose reduced and two patients terminated bevacizumab. Preliminary evidence of activity was demonstrated, with a disease control rate of 92% and response rate of 50%, including 1 CR and 5 PRs. There were five additional patients with stable disease. The median progression-free survival (PFS) was 49 weeks. These data support the potential to combine niraparib plus bevacizumab. Part 2 of the AVANOVA trial continues to enroll patients.

Frequent hospitalizations and ER visits during "watchful waiting" period support a change in clinical practice to maintenance therapy options for ovarian cancer patients
A retrospective study was conducted in the U.S. to characterize the treatment-free interval (or "watchful waiting") for patients newly diagnosed with ovarian cancer following completion of treatment with platinum-based chemotherapy. The analysis found that during the "watchful waiting" period, 30.1% of patients were admitted to the hospital as an in-patient, and 27.4% of patients visited the emergency room. These results suggest that patients with ovarian cancer often experience residual symptoms of their disease following the conclusion of chemotherapy.

Preliminary Phase 2 niraparib/pembrolizumab combination (TOPACIO) data shows activity in patients with platinum-resistant ovarian and triple-negative breast cancer
Data from a Phase 1 dose-escalation study of niraparib in combination with pembrolizumab in patients with platinum-resistant ovarian cancer (OC) or triple negative breast cancer (TNBC) was presented, along with preliminary response data from patients thus far treated in the Phase 2 TOPACIO study. In Phase 1, among the nine evaluable OC patients, five responded (partial or complete response) and four achieved stable disease. Three of the five responders had tumors that tested as wildtype BRCA 1/2 and three as PD-L1 negative (<1%). Of the four evaluable TNBC patients, three had stable disease and one patient came off study prior to her first assessment. The most common treatment related grade ≥3 adverse events occurring in ≥2 patients included anemia (35.7%), thrombocytopenia (35.7%), neutropenia (14.3%) and decreased platelet counts (14.3%). The recommended Phase 2 dose of niraparib was established as 200 mg oral niraparib once daily (increasing to 300 mg after cycle 2 in patients with no significant hematologic toxicities) in combination with 200 mg IV pembrolizumab on day 1 of each 21-day cycle.

The Phase 2 portion of the TOPACIO study is ongoing, and, as of the data cutoff, 36 OC patients and 47 TNBC patients were enrolled out of a planned 48 patients for each tumor cohort. Twenty-nine OC and 27 TNBC patients have been assessed by at least one scan with responses observed in both BRCA wild-type and PD-L1 negative tumors. Among the patients who had received at least one on-study scan, 6 OC patients and 5 TNBC patients had a ≥30% decrease in tumor lesion size and 10 of these 11 patients continue on therapy. Overall 52% OC and 63% TNBC patients who did not have progressive disease continue on therapy. No new safety signals were identified, and less than 7% of Phase 2 patients had experienced grade ≥3 thrombocytopenia during the first treatment cycle. Thirty patients (36.1%) enrolled in Phase 2 reported treatment-related grade ≥3 adverse events including anemia (8.4%), fatigue (6.0%), platelet count decrease (6.0%) and thrombocytopenia (6.0%).

TSR-042 (anti-PD-1 antibody)

TSR-042 safety profile and clinical activity demonstrated in heavily pre-treated patients
In a poster display session, preliminary safety, efficacy, receptor occupancy, and pharmacokinetic data for TSR-042, an anti-PD-1 antibody, were presented from a two-part Phase 1 study. No dose limiting toxicities were observed. Adverse events included fatigue, nausea, arthralgia, decreased appetite, and pruritus, which occurred in ≥10% of patients. In Part 1 (n=21), two patients with ovarian cancer and small cell lung cancer who were treated with TSR-042 experienced a partial response and five patients with fallopian tube or ovarian cancer had stable disease, two of whom are continuing treatment. Consistent with data reported for other anti-PD-1 antibodies, maximum direct and functional receptor occupancy was observed with both CD3+ binding and IL-2 stimulation assays at all three dose levels evaluated. In Part 2A (n=13), full receptor occupancy, as assessed by the assays used in Part 1, was maintained over 3 and 6 weeks at doses of 500 mg and 1,000 mg, respectively.

These preliminary findings indicate that TSR-042 is safe and well tolerated, with a safety and efficacy profile expected for an agent targeting the PD-1 pathway, evidence of linear PK, and sustained target engagement at administration intervals up to 6 weeks. The recommended Phase 2 dose was established at 500 mg Q3W for the first four cycles and 1000 mg Q6W thereafter. Serum concentrations of TSR-042 observed 3 weeks after the 500 mg dose were comparable to those observed 6 weeks after the 1000 mg dose. Patients with microsatellite instability high (MSI-H) and microsatellite stable endometrial cancer and non-small cell lung cancer are currently enrolling in the expansion phase of this study, and additional tumor types are planned for evaluation.

About ZEJULA (Niraparib)
Niraparib is marketed in the United States under trade name ZEJULA. ZEJULA (niraparib) is a poly(ADP-ribose) polymerase (PARP) inhibitor indicated for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. In preclinical studies, ZEJULA concentrates in the tumor relative to plasma, delivering greater than 90% durable inhibition of PARP 1/2 and a persistent antitumor effect.

ZEJULA (niraparib) Select Important Safety Information
Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML) was reported in patients treated with ZEJULA in all clinical studies. Discontinue ZEJULA if MDS/AML is confirmed.

Hematologic adverse reactions (thrombocytopenia, anemia and neutropenia) have been reported in patients treated with ZEJULA. Do not start ZEJULA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤ Grade 1). Monitor complete blood counts weekly for the first month, monthly for the next 11 months of treatment, and periodically after this time.

Hypertension and hypertensive crisis have been reported in patients treated with ZEJULA. Monitor blood pressure and heart rate monthly for the first year and periodically thereafter during treatment with ZEJULA. Closely monitor patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Based on its mechanism of action, ZEJULA can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for six months after receiving the final dose. Because of the potential for serious adverse reactions in breastfed infants from ZEJULA, advise a lactating woman not to breastfeed during treatment with ZEJULA and for one month after receiving the final dose.

In clinical studies, the most common adverse reactions included: thrombocytopenia, anemia, neutropenia, nausea, constipation, vomiting, abdominal pain/distension, mucositis/stomatitis, diarrhea, fatigue/asthenia, decreased appetite, headache, insomnia, nasopharyngitis, dyspnea, rash and hypertension.

Please see full Prescribing Information for additional Safety Information at www.zejula.com.

About TSR-042
TSR-042 is a monoclonal antibody targeting PD-1 and was developed as part of the collaboration between TESARO and AnaptysBio, Inc. This collaboration was initiated in March of 2014, and is focused on the development of monospecific antibody drugs targeting PD-1, TIM-3 (TSR-022), and LAG-3 (TSR-033), in addition to a bi-specific antibody drug candidate targeting PD-1/LAG-3.

On September 11, 2017 Novartis reported results from a Phase III study of 870 patients with stage III BRAF V600E/K mutation-positive melanoma after complete surgical resection treated with the combination of Tafinlar (dabrafenib) + Mekinist (trametinib) [1] (Press release, Novartis, SEP 11, 2017, View Source [SID1234520470]). Findings from the COMBI-AD study, which met its primary endpoint, found a statistically significant 53% reduction in the risk of death or recurrence in patients treated with the BRAF and MEK inhibitor combination therapy versus placebo (HR [hazard ratio]: 0.47 [95% CI (confidence interval): 0.39-0.58]; median not reached vs. 16.6 months, respectively; p<0.001), with no new safety signals reported [1]. Results of the study will be presented during the Presidential Symposium today at the European Society for Medical Oncology Congress (ESMO) (Free ESMO Whitepaper) in Madrid (Abstract #LBA6), and were simultaneously published in the New England Journal of Medicine[1],[2].

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“The efficacy and tolerability of Tafinlar in combination with Mekinist seen in this study represent an important step forward in the treatment of stage III BRAF V600E/K mutation-positive melanoma,” said lead investigator Axel Hauschild, MD, PhD, Professor of Dermatology, University Hospital Schleswig-Holstein, in Kiel, Germany. “These unprecedented results confirm a targeted therapy combination has the potential to transform the standard of care in the melanoma adjuvant setting.”

“While surgery is a curative option for most patients with localized melanoma, there is a need for improved standard of care therapies for patients – especially for stage III disease, which carries a higher risk of relapse and death following resection,” said Vas Narasimhan, Global Head Drug Development and Chief Medical Officer, Novartis. “The COMBI-AD data results address a significant unmet need in patients with stage III melanoma. We look forward to discussing the results with regulatory authorities worldwide.”

The COMBI-AD study evaluated Tafinlar + Mekinist among patients with stage III, BRAF V600E/K-mutant melanoma without prior anticancer therapy, randomized within 12 weeks of complete surgical resection. Patients received the Tafinlar (150 mg BID) and Mekinist (2 mg QD) combination (n = 438) or matching placebos (n = 432)[1]. After a median follow-up of 2.8 years, the primary endpoint was met in that combination therapy significantly reduced the risk of disease recurrence or death by 53% vs. placebo (HR: 0.47 [95% CI: 0.39-0.58]; median not reached vs. 16.6 months, respectively; p<0.001) [1]. The relapse-free survival benefit among the combination arm was observed across all patient subgroups, including stage III A, B and C. The estimated one-year, two-year, and three-year RFS were consistently higher than placebo (one year: 88% vs. 56%; two year: 67% vs. 44%; three year: 58% vs. 39%) [1]. The combination treatment group also saw an improvement in a key secondary endpoint of OS (HR: 0.57 [95% CI: 0.42-0.79] p=0.0006, which did not cross the predefined interim analysis boundary of p=0.000019 to claim statistical significance). Other secondary endpoints where the combination demonstrated a clinically meaningful benefit include DMFS (HR: 0.51 [95% CI: 0.40-0.65]), and FFR (HR: 0.47 [95% CI: 0.39-0.57]) [1]. Adverse events (AEs) were consistent with other Tafinlar + Mekinist studies, and no new safety signals were reported [1]. Of patients treated with the combination, 97% experienced an AE; 41% had grade 3/4 AEs and 26% had AEs leading to treatment discontinuation (vs. 88%, 14% and 3%, respectively, with placebo) [1]. In a separate study, Novartis presented Phase II results from BRF113928, showing efficacy for patients with BRAF V600E-mutant metastatic non-small cell lung cancer (NSCLC) without prior systemic therapy for metastatic disease when treated with the combination of Tafinlar + Mekinist (Abstract #LBA51) [3]. Among the 36 treatment-naïve patients receiving 150 mg of Tafinlar twice daily and 2 mg of Mekinist once daily, the overall response rate (ORR) was 64% (95% CI: 46%-79%). After a median follow-up of 15.9 months, median duration of response (DoR) was 10.4 months (95% CI: 8.3-17.9 months), and median progression-free survival (PFS) was 10.9 months (95% CI: 7.0-16.6 months) [3]. Median OS was 24.6 months (95% CI: 12.3 months-not estimable), two-year OS rate was 51% (95% CI: 33-67%)[3]. These study results were simultaneously published in The Lancet Oncology [4]. Findings from the study demonstrated clinically meaningful antitumor activity in patients who had not received prior systemic therapy and in patients who had received at least one platinum-based chemotherapy for their metastatic NSCLC, supporting recent approvals by the European Commission (EC) and US Food and Drug Administration (FDA). The most common AEs (incidence >20%) were pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough and dyspnea.

Additional poster and oral presentations related to the investigational use of Tafinlar and Mekinist in melanoma were also presented at the meeting, including:

Phase II Study of Neoadjuvant Dabrafenib + Trametinib (D+T) for Resectable Stage IIIB/C BRAF V600-Mutant Melanoma [Abstract #1220PD]
Five-year Efficacy and Safety Update From METRIC: Trametinib vs. Chemotherapy in Patients with BRAF V600E/K-Mutant Advanced or Metastatic Melanoma [Abstract #1226PD]
A Phase III Randomized, Double-Blind, Placebo-Controlled Study Comparing the Combination of PDR001 + Dabrafenib + Trametinib vs. Placebo + Dabrafenib + Trametinib in Treatment-Naïve Patients with Unresectable or Metastatic BRAF V600-Mutant Melanoma (COMBI-i) [Abstract #1259TiP]
KEYNOTE-022 Update: Phase I Study of First-Line Pembrolizumab (pembro) Plus Dabrafenib (D) and Trametinib (T) for BRAF-Mutant Advanced Melanoma [Abstract # 1216O]
A Phase II, Randomized, Open Label Study of Neoadjuvant Pembrolizumab with/without Dabrafenib and Trametinib (D+T) in BRAF V600-Mutant Resectable Stage IIIB/C/D Melanoma (NeoTrio Trial) [Abstract #1256TiP]
Dabrafenib and Trametinib Combination in Real Life Patients Including Brain Metastases: French Experience within MelBase [Abstract #1255P]
About COMBI-AD
The COMBI-AD study is a randomized, double-blind, placebo-controlled, Phase III study and included a total of 870 patients with stage III, BRAF V600E/K-mutant melanoma who had undergone prior complete surgical resection. Patients were treated for 12 months and stratified based on BRAF mutation (V600E vs. V600K) and stage (IIIA vs. IIIB vs. IIIC).

The primary endpoint was RFS. Secondary endpoints included OS, DMFS, FFR, and safety.

About Melanoma
There are about 200,000 new cases of melanoma diagnosed worldwide each year, approximately half of which have BRAF mutations. Gene tests can determine whether a tumor has a BRAF mutation [5],[6]. Patients who receive surgical treatment for melanoma may have a high risk of recurrence because melanoma cells can remain in the body after surgery[7]. Adjuvant therapy may be recommended for patients with high-risk melanoma to help reduce the risk of melanoma returning [7].

About Tafinlar + Mekinist Combination
Combination use of Tafinlar + Mekinist in patients with unresectable or metastatic melanoma who have a BRAF V600 mutation is approved in the US, EU, Australia, Canada and other countries.

The combination of Tafinlar + Mekinist is also approved for the treatment of metastatic non-small cell lung cancer (NSCLC) with a BRAF V600E mutation in the US and advanced NSCLC with a BRAF V600 mutation in the EU.

Tafinlar and Mekinist target different kinases within the serine/threonine kinase family – BRAF and MEK1/2, respectively – in the RAS/RAF/MEK/ERK pathway, which is implicated in NSCLC and melanoma, among other cancers. When Tafinlar is used with Mekinist, the combination has been shown to slow tumor growth more than either drug alone. The combination of Tafinlar + Mekinist is currently being investigated in an ongoing clinical trial program across a range of tumor types conducted in study centers worldwide.

The safety and efficacy profile of the Tafinlar + Mekinist combination has not yet been established outside of the approved indications.

Tafinlar and Mekinist are also indicated in more than 60 countries worldwide, including the US and EU, as single agents to treat patients with unresectable or metastatic melanoma with a BRAF V600 mutation.

Tafinlar + Mekinist Combination Important Safety Information
Tafinlar + Mekinist combination may cause serious side effects.

Tafinlar in combination with Mekinist should only be used to treat patients with a change (mutation) in the BRAF gene; therefore, doctors should test their patients before treatment, as patients without a BRAF mutation and with a RAS mutation can be at risk of increased cell proliferation in the presence of a BRAF inhibitor.

Doctors should also consider other treatment options for their patients if they had been previously treated with a BRAF inhibitor as single agent, as the limited data available have shown that the efficacy of Tafinlar + Mekinist is lower in these patients.

When Tafinlar is used in combination with Mekinist, or when Tafinlar is administered as monotherapy, it can cause new cancers (both skin cancer and non-skin cancer). Patients should be advised to contact their doctor immediately for any new lesions, changes to existing lesions on their skin, or signs and symptoms of other malignancies.

Tafinlar in combination with Mekinist, or Mekinist alone, can cause severe bleeding, and in some cases can lead to death. Patients should be advised to call their healthcare provider and get medical help right away if they have headaches, dizziness, or feel weak, cough up blood or blood clots, vomit blood or their vomit looks like “coffee grounds,” have red or black stools that look like tar, or any unusual signs of bleeding.

Tafinlar in combination with Mekinist, or either drug alone, can cause severe eye problems that can lead to blindness. Patients should be advised to call their healthcare provider right away if they get these symptoms of eye problems: blurred vision, loss of vision, or other vision changes, seeing color dots, halo (seeing blurred outline around objects), eye pain, swelling, or redness.

Tafinlar in combination with Mekinist, or Tafinlar alone, can cause fever which may be serious. When taking Tafinlar in combination with Mekinist, fever may happen more often or may be more severe. In some cases, chills or shaking chills, too much fluid loss (dehydration), low blood pressure, dizziness, or kidney problems may happen with the fever. Patients should be advised to call their healthcare provider right away if they get a fever above 38.5oC (101.3oF) while taking Tafinlar.

Tafinlar in combination with Mekinist, or Mekinist alone, can affect how well the heart pumps blood. A patient’s heart function should be checked before and during treatment. Patients should be advised to call their healthcare provider right away if they have any of the following signs and symptoms of a heart problem: feeling like their heart is pounding or racing, shortness of breath, swelling of their ankles and feet, or feeling lightheaded.

Tafinlar in combination with Mekinist, or Tafinlar alone, can cause abnormal kidney function or inflammation of the kidney. Abnormal kidney function may happen more often for patients with fever or too much fluid loss. Patients should be advised to call their healthcare provider right away if they have a fever above 38.5oC (101.3oF), decreased urine, fatigue, loss of appetite or discomfort in lower abdomen or back. Tafinlar has not been studied in patients with renal insufficiency (defined as creatinine > 1.5 x ULN) therefore caution should be used in this setting.

Tafinlar in combination with Mekinist, or Mekinist alone, can cause abnormal liver function. A patient may feel tired, lose appetite, yellow skin, dark urine colour, or discomfort in abdomen. The liver function abnormality needs to be assessed by laboratory test of the blood. Patients should consult their healthcare provider if they have such experience. Administration of Tafinlar or Mekinist should be done with caution in patients with moderate to severe hepatic impairment.

Elevations in blood pressure have been reported in association with Mekinist in combination with Tafinlar, or with Mekinist alone, in patients with or without pre-existing hypertension. Patients should be advised to monitor blood pressure during treatment with Mekinist and control potential hypertension by standard therapy, as appropriate.

Tafinlar in combination with Mekinist, or Mekinist alone, can cause inflammation of the lung tissue. Patients should notify their doctor if they experience any new or worsening symptoms of lung or breathing problems, including shortness of breath or cough.

Rash is a common side effect of Tafinlar in combination with Mekinist, or with Mekinist alone. Tafinlar in combination with Mekinist, or Mekinist alone, can also cause other skin reactions which can be severe, and may need to be treated in a hospital. Patients should be advised to call their healthcare provider if they get any of the following symptoms: skin rash that bothers them or does not go away, acne, redness, swelling, peeling, or tenderness of hands or feet, skin redness.

Tafinlar in combination with Mekinist, or Mekinist alone, can cause muscle breakdown, a condition called Rhabdomyolysis. Patients experiencing muscle pain, tenderness, weakness or a swelling of their muscles should contact their healthcare provide immediately.

Tafinlar in combination with Mekinist, or Tafinlar alone, can uncommonly cause an inflammation of the pancreas (pancreatitis). Patients should be promptly investigated if they experience unexplained abdominal pain and closely monitored if they re-start Tafinlar after a prior episode of pancreatitis.

Tafinlar in combination with Mekinist, or Mekinist alone, can cause blood clots in the arms or legs, which can travel to the lungs and can lead to death. Patients should be advised to get medical help right away if they have the following symptoms: chest pain, sudden shortness of breath or trouble breathing, pain in their legs with or without swelling, swelling in their arms or legs, or a cool or pale arm or leg.

Mekinist in combination with Tafinlar, or Mekinist alone, may increase the risk of developing holes in the stomach or intestine (gastrointestinal perforation). Treatment with Mekinist alone or in combination with Tafinlar should be used with caution in patients with risk factors for gastrointestinal perforation, including concomitant use of medications with a recognized risk of gastrointestinal perforation.

Tafinlar and Mekinist both can cause harm to an unborn baby when taken by a pregnant woman. Tafinlar can also render hormonal contraceptives ineffective.

The most common side effects of Tafinlar + Mekinist combination include fever, nausea, diarrhea, fatigue, chills, headache, vomiting, joint pain, high blood pressure, rash and cough. The incidence and severity of fever is increased when Mekinist is used in combination with Tafinlar.

Patients should tell their doctor of any side effect that bothers them or does not go away. These are not all of the possible side effects of Tafinlar + Mekinist combination. For more information, patients should ask their doctor or pharmacist.

Patients should take Tafinlar + Mekinist combination exactly as their health care provider tells them. Patients should not change their dose or stop taking Tafinlar + Mekinist combination unless their health care provider advises them to. Mekinist should be taken only once daily (either in the morning or evening, at the same time as Tafinlar). The first and second doses of Tafinlar should be taken approximately 12 hours apart. Patients should take Tafinlar + Mekinist at least 1 hour before or 2 hours after a meal. Do not take a missed dose of Tafinlar within 6 hours of the next dose of Tafinlar. Do not open, crush, or break Tafinlar capsules. Do not take a missed dose of Mekinist within 12 hours of the next dose of Mekinist.

Please see full Prescribing Information for Tafinlar and Mekinist.